Project Summary/Abstract Osteoporosis is highly prevalent among older adults in the United States, with approximately 10 million people affected. Nearly 50% of women over age 50 years and 25% of white men over age 60 years will suffer an osteoporotic fracture in their lifetimes, with significant consequences including death, difficulty in performing activities of daily living, loss of ambulatory ability, nursing home placement, and chronic pain. Bisphosphonates, a class of medications that are strong inhibitors of osteoclast bone remodeling, are effective for reducing fracture risk and the most commonly prescribed medications for osteoporosis treatment. FDA- approved bisphosphonates for treatment of osteoporosis include alendronate, risedronate, ibandronate, and zoledronic acid. These medications should not be continued indefinitely due to an increased risk of rare serious adverse events, such as atypical femoral fracture or osteonecrosis of the jaw, with therapy duration beyond 5 years. However, there is uncertainty with respect to the optimal duration of bisphosphonate therapy for individuals with osteoporosis. Furthermore, for individuals who stop treatment, the optimal duration of the ?drug holiday?, or period of time in which treatment is stopped before restarting treatment, is unknown. Bisphosphonates bind to bone and can remain bound for many years, thus resulting in residual pharmacological activity for years after discontinuation. However, binding affinity to bone varies among the bisphosphonates, and thus it is likely that the optimal drug holiday duration may vary depending on the particular bisphosphonate. The purpose of this proposed research is to systematically review the evidence on the duration of treatment for which fracture risk reduction has been demonstrated for each of the FDA- approved bisphosphonates for osteoporosis treatment and associated fracture risk reduction efficacy and change in bone mineral density (BMD) on bisphosphonate treatment, the impact of drugs holidays on fracture risk and BMD, and the safety (adverse events rates) associated with different durations of treatment (Aim 1); and to compare the effectiveness and cost-effectiveness of different treatment and drug holiday durations for each bisphosphonate for U.S. adults with osteoporosis (Aim 2). Our analyses would address key osteoporosis clinical care knowledge gaps and provide evidence to guide treatment duration and drug holiday duration decisions in clinical practice; and help enable a future R01 proposal to investigate approaches to translate findings about best treatment practices to the clinical setting to reduce osteoporosis-related morbidity and mortality. Our research team is ideally suited to perform this work; we have substantial experience and expertise in osteoporosis, systematic reviews/meta-analysis, and cost-effectiveness modeling, and a track record of successful collaboration.